Drug delivery technologies have enabled the development of many pharmaceutical products that improve patient health by enhancing the delivery of a therapeutic to its target site, minimizing ...off-target accumulation and facilitating patient compliance. As therapeutic modalities expanded beyond small molecules to include nucleic acids, peptides, proteins and antibodies, drug delivery technologies were adapted to address the challenges that emerged. In this Review Article, we discuss seminal approaches that led to the development of successful therapeutic products involving small molecules and macromolecules, identify three drug delivery paradigms that form the basis of contemporary drug delivery and discuss how they have aided the initial clinical successes of each class of therapeutic. We also outline how the paradigms will contribute to the delivery of live-cell therapies.
Acidogenic and aciduric bacteria have developed several survival systems in various acidic environments to prevent cell damage due to acid stress such as that on the human gastric surface and in the ...fermentation medium used for industrial production of acidic products. Common mechanisms for acid resistance in bacteria are proton pumping by F1–F0–ATPase, the glutamate decarboxylase system, formation of a protective cloud of ammonia, high cytoplasmic urease activity, repair or protection of macromolecules, and biofilm formation. The field of synthetic biology has rapidly advanced and generated an ever-increasing assortment of genetic devices and biological modules for applications in biofuel and novel biomaterial productions. Better understanding of aspects such as overproduction of general shock proteins, molecular mechanisms, and responses to cell density adopted by microorganisms for survival in low pH conditions will prove useful in synthetic biology for potential industrial and environmental applications.
Sequence‐defined polymers have been the object of many fascinating studies that focus on their implementation in both material and life science applications. In parallel, iterative synthetic ...methodologies have become more efficient, whereas the structure elucidation of these molecules is generally dependent on MS/MS analysis. Here, we report an alternative, simple strategy for the determination of the monomer order of uniform oligo(thioether ester)s. This approach, which relies on random cleavages of ester units within the macromolecular backbone via a basic treatment, enables the swift characterization of these macromolecules without the need for MS/MS. Consequently, this method can be used for decoding any information stored within the primary structure of oligoesters by means of ESI‐ or LC–MS. Finally, we speculate that a range of structurally diverse backbones could be susceptible towards this approach, which could promptly expand the library of chemically sequenceable macromolecules.
A strategy for the determination of the monomer order of sequence‐defined macromolecules by making use of ESI‐ or LC–MS is described. This approach, which relies on the introduction of random chain cleavages within the macromolecular backbone, enabled the rapid chemical sequencing of abiotic macromolecules.
Transforming how plastics are made, unmade, and remade through innovative research and diverse partnerships that together foster environmental stewardship is critically important to a sustainable ...future. Designing, preparing, and implementing polymers derived from renewable resources for a wide range of advanced applications that promote future economic development, energy efficiency, and environmental sustainability are all central to these efforts. In this Chemical Reviews contribution, we take a comprehensive, integrated approach to summarize important and impactful contributions to this broad research arena. The Review highlights signature accomplishments across a broad research portfolio and is organized into four wide-ranging research themes that address the topic in a comprehensive manner: Feedstocks, Polymerization Processes and Techniques, Intended Use, and End of Use. We emphasize those successes that benefitted from collaborative engagements across disciplinary lines.
Expert consensus recommends linear‐combination modeling (LCM) of 1H MR spectra with sequence‐specific simulated metabolite basis function and experimentally derived macromolecular (MM) basis ...functions. Measured MM basis functions are usually derived from metabolite‐nulled spectra averaged across a small cohort. The use of subject‐specific instead of cohort‐averaged measured MM basis functions has not been studied widely. Furthermore, measured MM basis functions are not widely available to non‐expert users, who commonly rely on parameterized MM signals internally simulated by LCM software. To investigate the impact of the choice of MM modeling, this study, therefore, compares metabolite level estimates between different MM modeling strategies (cohort‐mean measured; subject‐specific measured; parameterized) in a lifespan cohort and characterizes its impact on metabolite–age associations. 100 conventional (TE = 30 ms) and metabolite‐nulled (TI = 650 ms) PRESS datasets, acquired from the medial parietal lobe in a lifespan cohort (20–70 years of age), were analyzed in Osprey. Short‐TE spectra were modeled in Osprey using six different strategies to consider the MM baseline. Fully tissue‐ and relaxation‐corrected metabolite levels were compared between MM strategies. Model performance was evaluated by model residuals, the Akaike information criterion (AIC), and the impact on metabolite–age associations. The choice of MM strategy had a significant impact on the mean metabolite level estimates and no major impact on variance. Correlation analysis revealed moderate‐to‐strong agreement between different MM strategies (r > 0.6). The lowest relative model residuals and AIC values were found for the cohort‐mean measured MM. Metabolite–age associations were consistently found for two major singlet signals (total creatine (tCr)and total choline (tCho)) for all MM strategies; however, findings for metabolites that are less distinguishable from the background signals associations depended on the MM strategy. A variance partition analysis indicated that up to 44% of the total variance was related to the choice of MM strategy. Additionally, the variance partition analysis reproduced the metabolite–age association for tCr and tCho found in the simpler correlation analysis. In summary, the inclusion of a single high signal‐to‐noise ratio MM basis function (cohort‐mean) in the short‐TE LCM leads to more lower model residuals and AIC values compared with MM strategies with more degrees of freedom (Gaussian parametrization) or subject‐specific MM information. Integration of multiple LCM analyses into a single statistical model potentially allows to identify the robustness in the detection of underlying effects (e.g., metabolite vs. age), reduces algorithm‐based bias, and estimates algorithm‐related variance.
Linear‐combination modeling results of short‐TE PRESS from a 100‐subject healthy aging cohort using different strategies to model macromolecular (MM) signals (parameterized vs. measured) analyzed with Osprey. The choice of MM strategy accounts for a majority of the observed variance in the metabolite estimates for tNAA and GSH.
Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. From their initial discovery in the ...1960s, senescent cells have been hypothesized as potential contributors to the age-associated loss of regenerative potential. Here, we discuss recent evidence that implicates cellular senescence as a central regulatory mechanism of the aging process. We provide a comprehensive overview of age-associated pathologies in which cellular senescence has been implicated. We describe mechanisms by which senescent cells drive aging and diseases, and we discuss updates on exploiting these mechanisms as therapeutic targets. Finally, we critically analyze the use of senotherapeutics and their translation to the clinic, highlighting limitations and suggesting ideas for future applications and developments.
There is increasing evidence of the detrimental role of senescent cells in aging.Clearance of senescent cells has been shown to improve age-associated pathologies in animal models, leading to promising new clinical trials.Different mechanisms of senescent cells can be exploited pharmacologically to develop new therapeutic targets.
Stimuli-responsive polymers adapt to their surrounding environment. These polymers are capable of responding to a variety of external stimuli, which include optical, electrical, thermal, mechanical, ...redox, pH, chemical, environmental and biological signals. They are encountered in many environments. They can have a variety of architectures ( e.g. , copolymers, blocks, stars). They may be present as isolated macromolecules in a medium, as supramolecular assemblies, as smart coatings, as networks or some combination of these possibilities. This paper is concerned with the process of forming such polymers by radical polymerization with reversible addition fragmentation chain transfer (RAFT). RAFT polymerization has an advantage over most processes for reversible deactivation radical polymerization (RDRP) in its tolerance of a wide range of unprotected functionalities. Three basic strategies for forming stimuli-responsive polymers are considered: RAFT polymerization of functional monomers (a “grafting through” approach), the post-polymerization modification of RAFT-synthesized polymers (some combination of “grafting through”, “from” and “to”), and the use of functional RAFT agents and RAFT end-group transformation (often “grafting from”). Other syntheses involve combinations of these processes and of RAFT polymerization with other processes. We also consider the responsiveness of the thiocarbonylthio-functionality of macroRAFT agents in terms of their ability to directly initiate and control RAFT polymerization and to regulate the properties of RAFT-synthesized polymers.
Rewriting data stored on synthetic macromolecules is an interesting feature, even though it is considered as being quite challenging within the area of digital macromolecules. In this context, we ...initially studied a strategy for modifying the position tag of sequence‐encoded macromolecules in a reversible manner. The efficiency of this method, which relies on the orthogonal cleavage of a thioester moiety via aminolysis, was demonstrated by modifying parts of an exemplary sentence. Simultaneously, a novel algorithm was developed to ease the read‐out of macromolecular information by means of MS/MS techniques. This program, Oligoreader, can identify potential information‐containing macromolecules from a series of MS1 spectra, analyze the corresponding MS2 spectra, and finally decode the data. Consequently, the algorithm simplifies the entire read‐out process by avoiding any interference from the operator, which increases the potential for blind sequencing of uniform macromolecules.
The rewriting of information stored on synthetic macromolecules is achieved via the introduction of an editable position tag. The automated read‐out is facilitated by making use of an algorithm that is able to decode large portions of macromolecular information without interference from the operator.
RNA-based therapeutics have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown of pathological genes, expression of therapeutic proteins, and ...programmed gene editing. Due to the inherent instability and negative-charges of RNA molecules, RNA-based therapeutics can make the most use of delivery systems to overcome biological barriers and to release the RNA payload into the cytosol. Among different types of delivery systems, lipid-based RNA delivery systems, particularly lipid nanoparticles (LNPs), have been extensively studied due to their unique properties, such as simple chemical synthesis of lipid components, scalable manufacturing processes of LNPs, and wide packaging capability. LNPs represent the most widely used delivery systems for RNA-based therapeutics, as evidenced by the clinical approvals of three LNP-RNA formulations, patisiran, BNT162b2, and mRNA-1273. This review covers recent advances of lipids, lipid derivatives, and lipid-derived macromolecules used in RNA delivery over the past several decades. We focus mainly on their chemical structures, synthetic routes, characterization, formulation methods, and structure–activity relationships. We also briefly describe the current status of representative preclinical studies and clinical trials and highlight future opportunities and challenges.
The application of photochemistry to polymer and material science has led to the development of complex yet efficient systems for polymerization, polymer post‐functionalization, and advanced ...materials production. Using light to activate chemical reaction pathways in these systems not only leads to exquisite control over reaction dynamics, but also allows complex synthetic protocols to be easily achieved. Compared to polymerization systems mediated by thermal, chemical, or electrochemical means, photoinduced polymerization systems can potentially offer more versatile methods for macromolecular synthesis. We highlight the utility of light as an energy source for mediating photopolymerization, and present some promising examples of systems which are advancing materials production through their exploitation of photochemistry.
Seeing the light: Photochemistry is a powerful tool for mediating polymerization and material synthesis due to the inherent benefits of light as an energy source for activation. Some outstanding systems that utilize these benefits for polymerization and materials synthesis are reviewed.
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